Objective: To evaluate if APOE genotype and CSF biomarkers of AD co-pathology are associated with distinct rates of cognitive decline in PD subtypes.

Background: Cognitive impairment is a prevalent non-motor characteristic of Parkinson’s Disease (PD). GBA and LRRK2 mutations are two of the most common genetic risk factors for PD. A growing body of literature evaluates the influence of Apolipoprotein E (APOE) gene polymorphism and Alzheimer’s Disease( AD) co-pathology in PD patients, yielding conflicting findings, highlighting a substantial knowledge gap.

Method: In this retrospective longitudinal cohort study using the pooled data from two multicenter cohorts across North America and Europe, Participants were followed for up to 10 years. To determine whether APOE polymorphism in sPD and genetic forms of PD predict differential cognitive decline, we analyzed the effect of APOE genotype and baseline Cerebrospinal fluid (CSF) biomarkers like phosphorylated tau (pTau) and amyloid-beta 42 (Aβ42) on cognitive trajectories in PD subtypes using mixed-effects models.

Results: We studied 2,331 subjects, including 1,833 Sporadic PD (sPD), 124 GBA PD, 166 LRRK2 PD, and 208 Healthy controls (HC). The mean age of the cohort was 65.8 ± 8.9 years, and the proportion of males was 63%. The MoCA scores of the PD cohort were lower than those of HC at baseline (p < 0.001). In sPD, individuals with the APOE ε4 genotype experienced a more rapid decline in cognitive scores compared to those with the APOE ε3 genotype (p < 0.0001). In contrast, the APOE ε2 genotype exhibited a protective effect (p = 0.02). Individuals with lower baseline Aβ42 levels displayed a more rapid cognitive decline (p < 0.0001) in all groups. Conversely, higher baseline pTau levels were associated with an accelerated rate of cognitive decline, particularly in the sPD and LRRK2 groups. Factors that protect against cognitive decline include younger age, higher education, and female sex.

Conclusion: Our results emphasize that the effect of APOE polymorphism and CSF pTau on cognitive course vary by PD subtype, highlighting their distinct roles in disease progression. A  better understanding of the role of APOE and CSF biomarkers will not only elucidate the mechanisms underlying cognitive impairment in PD but also has the potential to facilitate disease-modifying interventions in clinical trials.

« Back to 2025 International Congress

MDS Abstracts - https://www.mdsabstracts.org/abstract/role-of-apoe-polymorphism-and-csf-markers-of-ad-co-pathology-in-the-cognitive-trajectories-of-sporadic-and-genetic-parkinsons-disease-a-longitudinal-cohort-study/